Knockdown of Dehydrodolichyl Diphosphate Synthase in the Drosophila Retina Leads to a Unique Pattern of Retinal Degeneration

Brandwine, Tal; Ifrah, Reut; Bialistoky, Tzofia; Zaguri, Rachel; Rhodes-Mordov, Elisheva; Mizrahi-Meissonnier, Liliana; Sharon, Dror; Katanaev, Vladimir L.; Gerlitz, Offer; Minke, Baruch

doi:10.3389/fnmol.2021.693967

Cited by 6 publications

(3 citation statements)

References 47 publications

(102 reference statements)

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“…Moreover this was accompanied by an increase of dehydrodolichyl diphosphate synthase (DHDDS, log 2 FC = 0.57, −log 10 p-value = 1.53), which uses FPP as a direct substrate. 47,48 This hypothesis is also supported by studies of mice lacking SQS in the liver, 4 which show signicant increase in FPP levels. 15 Since KY02111 was previously reported to inhibit the SQS-TMEM43 PPI, and that knockdown of SQS using siRNAs led to a decrease of TMEM43, we also anticipated a reduction of TMEM43 in cells with chemically reduced SQS levels.…”

Section: Resultsmentioning

confidence: 69%

Identification of non-conventional small molecule degraders and stabilizers of squalene synthase

Hoock¹,

Rossetti²,

Bilgin

et al. 2023

Preprint

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Squalene synthase (SQS) is an essential enzyme in the mevalonate pathway whose abundance and activity control cholesterol biosynthesis and homeostasis. Although catalytic inhibitors of SQS have been developed to attenuate cholesterol, none so far have been approved for therapeutic use. Herein we sought to develop SQS degraders using targeted protein degradation (TPD) as an approach to lower overall cellular cholesterol content. We found that KY02111, a small molecule ligand of SQS, could selectively cause SQS to degrade in a proteasome-dependent manner. In contrast, compounds based on the same scaffold linked to E3 ligase recruiting ligands led to SQS stabilization. Whole cell proteomic analysis found KY02111 to reduce only the levels of SQS, while lipidomic analysis determined that KY02111 treatment concomitantly reduced cellular cholesteryl ester content. SQS stabilizers were shown to shield SQS from its natural turnover without recruiting their matching E3 ligase. Our work shows that degradation of SQS is possible despite a challenging biological setting and lays the groundwork for future development of either SQS degrading or stabilizing probes.

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Section: Resultsmentioning

confidence: 69%

Identification of non-conventional small molecule degraders and stabilizers of squalene synthase

Hoock¹,

Rossetti²,

Bilgin

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Moreover this was accompanied by an increase of dehydrodolichyl diphosphate synthase (DHDDS, log 2 FC = 0.57, −log 10 p -value = 1.53), which uses FPP as a direct substrate. 47,48 This hypothesis is also supported by studies of mice lacking SQS in the liver, 4 which show significant increase in FPP levels. 15 Since KY02111 was previously reported to inhibit the SQS-TMEM43 PPI, and that knockdown of SQS using siRNAs led to a decrease of TMEM43, we also anticipated a reduction of TMEM43 in cells with chemically reduced SQS levels.…”

Section: Resultsmentioning

confidence: 73%

Identification of non-conventional small molecule degraders and stabilizers of squalene synthase

Hoock,

Rossetti,

Bilgin

et al. 2023

Chem. Sci.

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“…Although not a vertebrate, it should be noted that a Drosophila model of RP59 has been generated and characterized [ 63 ]. Drosophila offers a tractable model system readily amenable to genetic manipulation, and it contains a genetic ortholog ( CG10778 ) to the DHDDS gene.…”

Section: Mouse Models Of Rp59mentioning

confidence: 99%

Vertebrate Animal Models of RP59: Current Status and Future Prospects

Fliesler

Rao

Nguyen

et al. 2022

IJMS

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Retinitis pigmentosa-59 (RP59) is a rare, recessive form of RP, caused by mutations in the gene encoding DHDDS (dehydrodolichyl diphosphate synthase). DHDDS forms a heterotetrameric complex with Nogo-B receptor (NgBR; gene NUS1) to form a cis-prenyltransferase (CPT) enzyme complex, which is required for the synthesis of dolichol, which in turn is required for protein N-glycosylation as well as other glycosylation reactions in eukaryotic cells. Herein, we review the published phenotypic characteristics of RP59 models extant, with an emphasis on their ocular phenotypes, based primarily upon knock-in of known RP59-associated DHDDS mutations as well as cell type- and tissue-specific knockout of DHDDS alleles in mice. We also briefly review findings in RP59 patients with retinal disease and other patients with DHDDS mutations causing epilepsy and other neurologic disease. We discuss these findings in the context of addressing “knowledge gaps” in our current understanding of the underlying pathobiology mechanism of RP59, as well as their potential utility for developing therapeutic interventions to block the onset or to dampen the severity or progression of RP59.

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Knockdown of Dehydrodolichyl Diphosphate Synthase in the Drosophila Retina Leads to a Unique Pattern of Retinal Degeneration

Cited by 6 publications

References 47 publications

Identification of non-conventional small molecule degraders and stabilizers of squalene synthase

Identification of non-conventional small molecule degraders and stabilizers of squalene synthase

Identification of non-conventional small molecule degraders and stabilizers of squalene synthase

Vertebrate Animal Models of RP59: Current Status and Future Prospects

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